Section 1 -

Arrhythmogenesis and Sudden Death Gaetano Thiene and Cristina Basso Institute of Pathological Anatomy, University of Padua Medical School Padua , Italy

Cardiovascular diseases account for 40% of all deaths in the Western countries, and nearly two third of them occur suddenly. Sudden cardiovascular deaths may be "mechanical", in the setting of pulmonary thromboembolism or aortic rupture, or "electrical" due to an abrupt arrhythmic disorder leading to cardiac arrest [1]. Nearly 10% of all sudden cardiovascular deaths are mechanical, whereas the remaining 90% are "electrical". The arrhythmic mechanism leading to cardiac arrest is ventricular fibrillation in 70% of cases, ventricular tachycardia in 15%, heart block with asystole in 10% and electro-mechanical dissociation in 5%. Defibrillator, whether external or implantable, is nowadays available to convert ventricular fibrillation to sinus rhythm and to "resuscitate" the patient. This awareness has fundamental impact for cardiac arrest treatment and sudden death prevention. Malignant arrhythmogenesis, accounting for cardiac arrest, may find an explanation in the following substrates: Ischemic heart disease. It accounts for 60% of all causes of sudden death in adults and 25% in the young (<35 years) [2]. Coronary occlusive thrombosis (plaque rupture or erosion), embolism, dissection [3] or transient coronary occlusion by spasm superimposed to a critical coronary stenosis can precipitate an acute ischemic attack, as to jeopardize the electrical myocardial order and trigger ventricular fibrillation. Previous myocardial infarction, with scarring and impaired ejection fraction, in the setting of an ischemic milieu, may account for life-threatening ventricular arrhythmias. Congenital coronary artery anomalies, particularly the origin of a coronary artery from a wrong aortic sinus, are also at high risk of myocardial ischemia during effort [4]. Cardiomyopathies . They account for nearly 10% of sudden cardiac deaths in the adult and 40% in the young [1]. Arrhythmogenic right ventricular cardiomyopathy, by definition a heart muscle disease with a great propensity to arrhythmias of right ventricular origin, is featured by progressive fibro-fatty replacement of the right ventricular myocardium [5, 6]. It is an autosomal, mostly dominant hereditary disease and it has been recently demonstrated to be a "desmosomal cardiomyopathy" due to gene mutations encoding defective proteins of cell junction (plakoglobin, desmoplakin, plakophilin, desmoglein, desmocolin) [7]. It is a major cause of sudden death in young athletes, in so far as effort may trigger malignant arrhythmias because of overload and dilatation of ventricular cavities. Hypertrophic cardiomyopathy, an autosomal dominant hereditary heart muscle disease of the left ventricle, is also at high risk of sudden death in the young and athletes [8]. The mutations reside in genes encoding sarcomere proteins, like ß-myosin heavy chain, myosin binding protein C, α-tropomyosin, troponin I and T [7]. The arrhythmias are triggered by the combination of myocardial disarray, a peculiar histological disarrangement of the myocytes, and myocardial ischemia due to impaired coronary perfusion because of compression of the intramural small vessels [9]. Inflammatory cardiomyopathies (namely myocarditis) are also a major cause of sudden death (nearly 10% in the young). Viruses, especially cardiotropic viruses like enterovirus, are the usual culprit. Viral etiology is nowadays easy to diagnose at postmortem thanks to molecular pathology tools (PCR and RT-PCR) [10]. Valve disease . Aortic stenosis, whether congenital or acquired, is at risk of sudden death in case of high transvalvular gradient with concentric left ventricular hypertrophy. The arrhythmic mechanism is basically ischemic, due to impaired coronary perfusion in the subendocardium. Mitral valve prolapse is also a nightmare in terms of sudden death risk. Only cases with mucoid degeneration and cusp thickening are life-threatening. The mechanism of cardiac arrest is not mechanical due to valve incompetence or chordal rupture, but arrhytmic due to patchy fibrosis of the left ventricle or fibrofatty replacement of the right ventricle, both unexplained so far. Conduction system abnormalities. In this subcategory, the leading cause of sudden death is ventricular preexcitation, due to accessory av pathway (Wolff-Parkinson-White syndrome) or enhanced av conduction (Lown-Ganong-Levine syndrome) [11]. In both conditions, the alleged mechanism accounting for arrhythmic cardiac deaths is the onset of atrial fibrillation which, in the absence of the physiologic delay of av conduction, through the working myocardium accessory pathway, may turn into ventricular fibrillation. Nearly 85-90% of sudden cardiac deaths find an explanation in a cardiac substrate (mors cum materia) [10, 12]. In the remaining 10-15% the heart is grossly and histologically normal (mors sine materia). In the latter condition, also known as idiopathic ventricular fibrillation, the arrhythmic mechanism relies in abnormal depolarization-repolarization properties of the myocytes, due to genetic defects of ion channels. Long and short QT syndromes are characterized mostly by potassium channel disorders. In Brugada syndrome, featured by non ischemic ST segment elevation with right bundle branch block, sodium channels are genetically impaired. Genetic defects in the sodium pump may account also for familiar av block (progressive cardiac conduction defect or Lenegre disease) [13]. Mutations of ryanodine cardiac receptor, located in the smooth reticulum and responsible for calcium release and excitation-contraction coupling, account for catecholaminergic ventricular tachycardia [14, 15]. It is a life-threatening electrical disorder, characterized by normal basal ECG and onset of ventricular tachycardia/fibrillation during effort or emotion, when the threshold of 120-125 cardiac beats/m is exceeded. This disorder explains up to 15% of sudden deaths sine materia [16]. Sudden infant death syndrome and still births, in a few cases, have been also ascribed to genetic disorders of ion channels and ryanodine cardiac receptor. Overall, 30-40% of the disease at risk of sudden death in the young are genetically, potentially recurrent cardiac disorders. Targets to treat and prevent life-threatening arrhythmias consist of: a) switch off arrhythmias with defibrillator; b) inhibit the onset of arrhythmias with drugs or ablation; c) avoid triggers like effort or emotion; d) hinder the recurrence of the disease with genetic counseling and/or therapy. The pathologist mission is to pursue the correct diagnosis and, when dealing with a genetic disease, fostering a widespread investigation of first degree familiar members to: detect asymptomatic carriers reassure non carriers adopt therapeutic and preventive measures perform genetic screening and counselling An interdisciplinary approach through a collaboration among the cardiologist, genetist, pathologist and sport physician is mandatory. References Thiene G, Basso C. Cardiovascular causes of sudden death. In: Silver MD, Gotlieb AI, Schoen FJ. Cardiovascular pathology. 3rd Edition. Philadelphia, Churchill Livingstone 2001;326-374. Corrado D, Basso C, Poletti A, Angelini A, Valente M, Thiene G. Sudden death in the young. Is acute coronary thrombosis the major precipitating factor ? Circulation 1994;90:2315-2323 Basso C, Morgagni GL, Thiene G. Spontaneous coronary artery dissection: a neglected cause of acute myocardial ischaemia and sudden death. Heart 1996;75:451-454 Basso C, Maron BJ, Corrado D, Thiene G. Clinical profile of congenital coronary artery anomalies with origin from the wrong aortic sinus leading to sudden death in young competitive athletes. J Am Coll Cardiol 2000;35:1493-501 Thiene G, Nava A, Corrado D, Rossi L, Pennelli N. Right ventricular cardiomiopathy and sudden death in young people. New Engl J Med 1988;318:129-133 Basso C, Thiene G, Corrado D, Angelini A, Nava A, Valente M. Arrhythmogenic right ventricular cardiomyopathy: dysplasia, dystrophy or myocarditis ? Circulation 1996;94:983-991 Thiene G, Basso C, Corrado D. Cardiomyopathies: is it time for a molecular classification? Eur Heart J 2004;25:1772-1775 Corrado D, Basso C, Schiavon M, Thiene G. Screening for hypertrophic cardiomyopathy in young athletes. New Engl J Med 1998;339:364-9 Basso C, Thiene G, Corrado D, Buja G, Melacini P, Nava A. Hypertrophic cardiomyopathy and sudden death in the young: pathologic evidence of myocardial ischemia. Hum Pathol 2000;84:245-250 Basso C, Calabrese F, Corrado D, Thiene G. Postmortem diagnosis in sudden cardiac death victims: macroscopic, microscopic and molecular findings. Cardiovasc Res 2001;50:290-300 Basso C, Corrado D, Rossi L, Thiene G. Ventricular Preexcitation in Children and Young Adults : Atrial Myocarditis as a Possible Trigger of Sudden Death. Circulation 2001;103: 269-275 Corrado D, Basso C, Thiene G. Sudden cardiac death in young people with apparently normal heart. Cardiovasc Res 2001;50:399-408 Corrado D, Basso C, Buja GF, Nava A, Rossi L, Thiene G. Right bundle branch block, right precordial ST-segment elevation and sudden death in young people. Circulation 2001;103:710-717 Tiso N, Stephan DA, Nava A, Bagattin A, Devaney JM, Stanchi F, Larderet G, Brahmbhatt, Brown K, Bauce B, Muriago M, Basso C, Thiene G, Danieli GA, Rampazzo A. Identification of mutations in the cardiac ryanodine receptor gene in families affected with arrhythmogenic right ventricular cardiomyopathy type 2 (ARVD2). Hum Mol Gen 2001;10:189-194 Bauce B, Rampazzo A, Basso C, Bagattin A, Daliento L, Tiso N, Turrini P, Thiene G, Danieli GA, Nava A. Screening for ryanodine receptor type 2 mutations in families with effort-induced polymorphic ventricular arrhythmias and sudden death. J Am Coll Cardiol 2002;40:341-349 Tester DJ, Spoon DB, Valdivia HH, Makielski JC, Ackerman MJ. Targeted mutational analysis of the RyR2-encoded cardiac ryanodine receptor in sudden unexplained death: a molecular autopsy of 49 medical examiner/coroner's cases. Mayo Clin Proc. 2004;79:1380-1384